Synucleinopathy is a neuropathological finding in a subset of chronic, mostly age-related, neurodegenerative disorders that are characterized by degeneration of the dopaminergic and other neural systems, motor disabilities, cognitive impairment, and formation of specific intraneuronal or intraglial accumulations, such as Lewy bodies (LBs) or Lewy neurites. (McKeith et al., Neurology 47:1113-1124 (1996)). Synucleinopathies include Lewy body diseases, such as Parkinson's disease (including idiopathic Parkinson's disease), diffuse Lewy body disease (DLBD) (also known as dementia with Lewy bodies (DLB)), Lewy body variant of Alzheimer's disease (LBV), Alzheimer's and Parkinson disease comorbidity, and pure autonomic failure, as well as multiple system atrophy (MSA; e.g., olivopontocerebellar atrophy, striatonigral degeneration and Shy-Drager syndrome). Several nonmotor signs and symptoms are thought to be harbingers for synucleinopathies in the prodromal phase of the diseases (i.e., the presymptomatic, subclinical, preclinical, or premotor period). Such early signs include, for example, REM sleep behavior disorder (RBD), loss of smell and constipation (Mahowald et al., Neurology 75:488-489 (2010)). Lewy body diseases continue to be a common cause for movement disorders and cognitive deterioration in the aging population (Galasko et al., Arch. Neurol. 51:888-895(1994)).
Alpha-synuclein is part of a large family of proteins including beta- and gamma-synuclein and synoretin. Alpha-synuclein is expressed in the normal state, and some of it is located in presynaptic terminals, where it regulates vesicular fusion to the synaptic membrane and is believed to play a role in neural function, plasticity, learning, and memory. The protein can aggregate to form insoluble fibrils in pathological conditions, and disorders with histological presence of such aggregates in the brain are therefore called synucleinopathies. Several studies have implicated alpha-synuclein with a central role in Parkinson's disease pathogenesis. For example, alpha-synuclein accumulates in Lewy bodies (LBs) (Spillantini et al., Nature 388:839-840 (1997); Takeda et al., J. Pathol. 152:367-372 (1998); Wakabayashi et al., Neurosci. Lett. 239:45-48 (1997)). Mutations in the alpha-synuclein gene co-segregate with rare familial forms of parkinsonism (Kruger et al., Nature Gen. 18:106-108 (1998); Polymeropoulos, et al., Science 276:2045-2047 (1997)). Overexpression of alpha-synuclein in transgenic mice (Masliah et al., Science 287:1265-1269 (2000)) and Drosophila (Feany et al., Nature 404:394-398 (2000)) mimics several pathological aspects of Lewy body disease. In addition, it has been suggested that soluble oligomers of alpha-synuclein may be neurotoxic (Conway et al., Proc. Nat'l Acad. Sci. USA 97:571-576 (2000); Volles et al., J. Biochem. 42:7871-7878 (2003)). The accumulation of alpha-synuclein with similar morphological and neurological alterations in species and animal models as diverse as humans, mice, and flies suggests that this molecule contributes to the development of Lewy body disease.
Antibodies to alpha-synuclein, or fragments of alpha-synuclein to induce such antibodies, have been proposed for methods of immunotherapy against synucleinopathies such as Lewy body disease. However, brain penetration of antibodies may be limited by the blood-brain barrier (BBB).